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Endogenous and Exogenous Factors Affecting Lipoprotein Lipase Activity

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Endogenous and Exogenous Factors Affecting Lipoprotein Lipase Activity Umeå University Medical Dissertations, New Series No. 1669 Endogenous and exogenous factors affecting lipoprotein lipase activity Mikael Larsson Department of Medical Biosciences, Physiological Chemistry Umeå 2014 Copyright © Mikael Larsson 2014 Responsible publisher under Swedish law: the Dean of the Medical Faculty This work is protected by the Swedish Copyright Legislation (Act 1960:729) ISBN: 978-91-7601-115-7 ISSN: 0346-6612 E-version available at http:// http://umu.diva-portal.org/ Printed by: Cityprint I Norr AB Umeå, Sweden 2014 Abstract Individuals with high levels of plasma triglycerides are at high risk to develop cardiovascular disease (CVD), currently one of the major causes of death worldwide. Recent epidemiological studies show that loss-of-function mutations in the APOC3 gene lower plasma triglyceride levels and reduce the incidence of coronary artery disease. The APOC3 gene encodes for apolipoprotein (APO) C3, known as an inhibitor of lipoprotein lipase (LPL) activity. Similarly, a common gain-of-function mutation in the LPL gene is associated with reduced risk for CVD. LPL is central for the metabolism of lipids in blood. The enzyme acts at the endothelial surface of the capillary bed where it hydrolyzes triglycerides in circulating triglyceride-rich lipoproteins (TRLs) and thereby allows uptake of fatty acids in adjacent tissues. LPL activity has to be rapidly modulated to adapt to the metabolic demands of different tissues. The current view is that LPL is constitutively expressed and that the rapid modulation of the enzymatic activity occurs by some different controller proteins. Angiopoietin-like protein 4 (ANGPTL4) is one of the main candidates for control of LPL activity. ANGPTL4 causes irreversible inactivation through dissociation of the active LPL dimer to inactive monomers. Other proteins that have effects on LPL activity are the APOCs which are surface components of the substrate TRLs. APOC2 is a well- known LPL co-factor, whereas APOC1 and APOC3 independently inhibit LPL activity. Given the important role of LPL for triglyceride homeostasis in blood, the aim of this thesis was to find small molecules that could increase LPL activity and serve as lead compounds in future drug discovery efforts. Another aim was to investigate the molecular mechanisms for how APOC1 and APOC3 inhibit LPL activity. Using a small molecule screening library we have identified small molecules that can protect LPL from inactivation by ANGPTL4 during incubations in vitro. Following a structure-activity relationship study we have synthesized lead compounds that more efficiently protect LPL from inactivation by ANGPTL4 in vitro and also have dramatic triglyceride-lowering properties in vivo. In a separate study we show that low concentrations of fatty acids possess the ability to prevent inactivation of LPL by ANGPTL4 under in vitro conditions. With regard to APOC1 and APOC3 we demonstrate that when bound to TRLs, these apolipoproteins prevent binding of LPL to the lipid/water interface. This results in decreased lipolysis and in an increased susceptibility of LPL to inactivation by ANGPTL4. We demonstrate that hydrophobic amino acid residues that are centrally located in the APOC3 molecule are critical for attachment of this protein to lipid emulsion particles and consequently for inhibition of LPL activity. In summary, this work has identified a lead compound that protects LPL from inactivation by ANGPTL4 in vitro and lowers triglycerides in vivo. In addition, we propose a molecular mechanism for inhibition of LPL activity by APOC1 and APOC3. i Table of Contents Abbreviations iii List of papers iv Introduction 1 Transport and metabolism of exogenous lipids 2 Transport and metabolism of endogenous lipids 3 Reverse cholesterol transport 4 Dyslipidemia and cardiovascular disease 5 Determinants of plasma triglyceride metabolism 6 Lipoprotein lipase 6 Regulation of lipoprotein lipase activity 10 Lipoprotein lipase in atherosclerosis 11 Angiopoietin-like proteins 13 GPI-anchored HDL-binding protein 1 16 Apolipoproteins 17 Apolipoprotein A1 18 Apolipoprotein B 18 Apolipoprotein C1 19 Apolipoprotein C2 20 Apolipoprotein C3 22 Apolipoprotein E 24 Apolipoprotein A5 26 Aims of the thesis 27 Results and discussion 28 Paper I 28 Paper II 32 Paper III and IV 33 Conclusions 39 References 40 Acknowledgements 55 ii Abbreviations ABCA1 – ATP-binding cassette transporter A1 ANGPTL – angiopoietin-like protein APO – apolipoprotein ATP – adenosine triphosphate CETP – cholesteryl ester transfer protein CHD – coronary heart disease CVD – cardiovascular disease ER – endoplasmic reticulum GPI – glycosylphosphatidylinositol GPIHBP1 – GPI-anchored HDL-binding protein 1 HDL – high-density lipoprotein HTS – high-throughput screening IDL – intermediate-density lipoprotein LCAT – lecithin-cholesterol acyltransferase LDL – low-density lipoprotein LDLR – low-density lipoprotein receptor LMF1 – lipase maturation factor 1 LPL – lipoprotein lipase LRP1 – low-density lipoprotein receptor-related protein 1 LXR – liver X receptor LY6 – lymphocyte antigen 6 MTP – microsomal triglyceride transfer protein PPARs – peroxisome proliferator-activated receptors PTLP – phospholipid transfer protein SAR – structure–activity relationship SR-B1 – scavenger receptor class B member 1 TG – triglyceride TRL – triglyceride-rich lipoproteins VLDL – very low-density lipoprotein iii Paper I Apolipoproteins C-I and C-III inhibit lipoprotein lipase activity by displacement of the enzyme from lipid droplets Larsson, M., Vorrsjö, E., Talmud, P., Lookene, A., and Olivecrona, G. (2013) The Journal of Biological Chemistry 288(47):33997-4008 Paper II Fatty acids bind tightly to the N-terminal domain of angiopoietin-like protein 4 and modulate its interaction with lipoprotein lipase Robal, T., Larsson, M., Martin, M., Olivecrona, G., and Lookene, A. (2012) The Journal of Biological Chemistry 287(35):29739-52 Paper III Identification of a small molecule that stabilizes lipoprotein lipase in vitro and lowers triglycerides in vivo Larsson, M., Caraballo, R., Ericsson, M., Lookene, A., Enquist, P. A., Elofsson, M., Nilsson, S. K., and Olivecrona, G. (2014) Biochemical and Biophysical Research Communications 25;450(2):1063-9 Paper IV Structure-activity relationships of small molecules lowering plasma triglycerides Caraballo, R., Larsson, M., Nilsson, S.K., Ericsson, M., Qian, W., Nguyen, N.P., Kindahl, T., Svensson, R., Mastej, M., Artursson, P., Olivecrona, G., Enquist, P.A., and Elofsson, M. Manuscript iv Introduction Triglycerides (or triacylglycerols) are the most abundant dietary lipids. They are used as source of energy in most tissues or for storage in adipose tissue. Triglycerides are non-polar esters made up of glycerol and long-chain fatty acids that are incapable of entering cells on their own. Hydrolysis of the ester bonds, catalysed by enzymes called lipases is therefore needed. By the action of lipases fatty acids are released from the glycerol backbone so that the polar lipolysis products (fatty acids and monoglycerides) can cross the plasma membrane of cells and be used for metabolic purposes. Besides serving as a source of energy, fatty acids are active substances and function as signal molecules. When in excess, fatty acids may lead to cellular dysfunction and even cell death. In contrast triglycerides are inert. Therefore fatty acids in excess are re-esterified to form triglycerides that in turn enable safe storage in intracellular lipid droplets and/or transport in lipoproteins in blood. Lipoproteins are macromolecular assemblies of lipids and proteins composed of phospholipids and cholesterol that form spherical monolayers covering a core of triglycerides and cholesteryl esters. The polar headgroups of the phospholipids and the hydroxyl groups of cholesterol compose a hydration shell that surrounds the hydrophobic core. Apolipoproteins (APOs) are specific protein components of the surface layer of lipoproteins. They regulate lipoprotein metabolism by serving as receptor ligands and cofactors/inhibitors of enzymes. Lipoproteins are divided into subclasses based on their density (Table 1). The different lipoprotein classes have distinct origins and functions and compose a dynamic system that maintains lipid homeostasis in blood. Chylomicrons and VLDL are the largest lipoproteins. They are responsible for the transport of triglycerides in blood and are therefore important carriers of energy to cells, while LDL and HDL mainly serve as carriers of cholesterol. Disturbances in lipid homeostasis are associated with common human diseases such as obesity, insulin resistance and diabetes. Ultimately, lipid disorders may lead to cardiovascular disease with fatal outcomes. 1 Chylomicrons VLDL IDL LDL HDL 0.95- 1.006- 1.019- 1.063- Density (g/cm3) <0.95 1.006 1.019 1.063 1.21 Diameter (nm) 75-1200 30-80 25-35 18-25 5-12 Chemical composition (% dry weight) Protein 1-2 10 18 25 33 Triglyceride 83 50 31 10 8 Cholesterol and 8 22 29 46 30 cholesteryl ester Phospholipid 7 18 22 22 29 Apolipoproteins B48, A, C, E B100, C, E B100, C, E B100 A, C, E Table 1. Characteristics and composition of human lipoprotein classes [1]. Transport and metabolism of exogenous lipids After a meal, dietary triglycerides enter the gut in large insoluble lipid droplets. Bile salts help to emulsify these lipid droplets into smaller entities and thereby increase the accessible surface. The protein colipase binds and promotes hydrolysis of the triglycerides by pancreatic lipase [2]. The lipolysis products (fatty
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